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Zhang F, Yan M, Xiao L, Jiang C, Li C, Li X, Du M, Wang C, Li J, Ning C. Hyperechoic Spots in the Renal Medulla as a Potential Indicator of Early Gouty Nephropathy. Am J Nephrol 2024; 55:657-671. [PMID: 39197426 DOI: 10.1159/000541110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2024] [Accepted: 08/20/2024] [Indexed: 09/01/2024]
Abstract
INTRODUCTION The aim of the study was to explore the causes and clinical significance of hyperechoic renal medulla observed by ultrasonography in patients with primary gout. METHODS This study included 2,107 patients with primary gout treated in the Gout Clinic of our hospital from 2016 to 2022. The clinical data and biochemical data of these patients were collected and analyzed. According to the presence or absence of punctate hyperechogenicity in the renal medulla on ultrasound examination, the patients were divided into the hyperechoic medulla (HM) and the normal hypoechoic medulla (NM) groups, and the HM group was further divided into the partial HM (P-HM) and fulfilled HM (F-HM) subgroups according to the distribution range of hyperechogenicity. RESULTS Among the 2,107 patients with primary gout, 380 had hyperechoic renal medulla on renal ultrasound, including 106 patients with F-HM and 274 with P-HM. There were significant differences in the gout duration, urate arthropathy number, serum urate (SU) level, clinical tophi number, blood urea nitrogen, serum creatinine (sCr), and estimated glomerular filtration rate between the HM and NM groups or between the F-HM and P-HM subgroups (p < 0.05). Multivariate regression analysis showed that the presence of HM was positively correlated with gout duration, urate arthropathy number, gout attack frequency, SU, and sCr. The number of clinical tophi and sCr were closely related to F-HM. CONCLUSION Ultrasound examination showed that a high medulla echo in patients with gout was often related to renal function damage. P-HM may be a transitory condition between NM and F-HM in patients with gout.
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Affiliation(s)
- Fangfang Zhang
- Abdominal Ultrasound Department of Qingdao University Affiliated Hospital, Qingdao, China
| | - Mengmeng Yan
- Abdominal Ultrasound Department of Qingdao University Affiliated Hospital, Qingdao, China
| | - Lishan Xiao
- Abdominal Ultrasound Department of Qingdao University Affiliated Hospital, Qingdao, China
| | - Caiyun Jiang
- Abdominal Ultrasound Department of Qingdao University Affiliated Hospital, Qingdao, China
| | - Changgui Li
- Shandong Provincial Key Laboratory of Metabolic Diseases and Qingdao Key Laboratory of Gout, The Affiliated Hospital of Qingdao University, Qingdao, China
- Department of Endocrinology and Metabolism, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xiaoli Li
- Department of Radiology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Meixia Du
- Abdominal Ultrasound Department of Qingdao University Affiliated Hospital, Qingdao, China
| | - Can Wang
- Shandong Provincial Key Laboratory of Metabolic Diseases and Qingdao Key Laboratory of Gout, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Jun Li
- Abdominal Ultrasound Department of Qingdao University Affiliated Hospital, Qingdao, China
| | - Chunping Ning
- Abdominal Ultrasound Department of Qingdao University Affiliated Hospital, Qingdao, China
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Otani N, Ouchi M, Mizuta E, Morita A, Fujita T, Anzai N, Hisatome I. Dysuricemia-A New Concept Encompassing Hyperuricemia and Hypouricemia. Biomedicines 2023; 11:biomedicines11051255. [PMID: 37238926 DOI: 10.3390/biomedicines11051255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 04/20/2023] [Accepted: 04/21/2023] [Indexed: 05/28/2023] Open
Abstract
The importance of uric acid, the final metabolite of purines excreted by the kidneys and intestines, was not previously recognized, except for its role in forming crystals in the joints and causing gout. However, recent evidence implies that uric acid is not a biologically inactive substance and may exert a wide range of effects, including antioxidant, neurostimulatory, proinflammatory, and innate immune activities. Notably, uric acid has two contradictory properties: antioxidant and oxidative ones. In this review, we present the concept of "dysuricemia", a condition in which deviation from the appropriate range of uric acid in the living body results in disease. This concept encompasses both hyperuricemia and hypouricemia. This review draws comparisons between the biologically biphasic positive and negative effects of uric acid and discusses the impact of such effects on various diseases.
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Affiliation(s)
- Naoyuki Otani
- Department of Cardiology, Dokkyo Medical University Nikkyo Medical Center, Nikko 321-1298, Tochigi, Japan
| | - Motoshi Ouchi
- Department of Pharmacology and Toxicology, Dokkyo Medical University School of Medicine, Mibu 321-0293, Tochigi, Japan
| | - Einosuke Mizuta
- Department of Cardiology, Sanin Rosai Hospital, Yonago 683-8605, Tottori, Japan
| | - Asuka Morita
- Department of Pharmacology and Toxicology, Dokkyo Medical University School of Medicine, Mibu 321-0293, Tochigi, Japan
| | - Tomoe Fujita
- Department of Pharmacology and Toxicology, Dokkyo Medical University School of Medicine, Mibu 321-0293, Tochigi, Japan
| | - Naohiko Anzai
- Department of Pharmacology and Toxicology, Dokkyo Medical University School of Medicine, Mibu 321-0293, Tochigi, Japan
- Department of Pharmacology, Chiba University Graduate School of Medicine, Chiba 260-8670, Chiba, Japan
| | - Ichiro Hisatome
- Yonago Medical Center, National Hospital Organization, Yonago 683-0006, Tottori, Japan
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3
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Piani F, Johnson RJ. Does gouty nephropathy exist, and is it more common than we think? Kidney Int 2021; 99:31-33. [PMID: 33390238 DOI: 10.1016/j.kint.2020.10.015] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2020] [Revised: 10/11/2020] [Accepted: 10/15/2020] [Indexed: 01/06/2023]
Abstract
Gout is present in one third of subjects with CKD but is usually an exclusion criterion in clinical trials investigating the role of uric acid in kidney disease. Bardin et al. report that one third of gouty subjects have hyperechoic medullas by ultrasound (consistent with crystalline deposits) that correlates with increased risk for hypertension and kidney dysfunction and which were not observed in >500 controls. If validated, a "gouty nephropathy" from microcrystalline deposits could be an important, unrecognized cause of CKD.
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Affiliation(s)
- Federica Piani
- Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
| | - Richard J Johnson
- Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
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4
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Hyperuricemia in Kidney Disease: A Major Risk Factor for Cardiovascular Events, Vascular Calcification, and Renal Damage. Semin Nephrol 2020; 40:574-585. [PMID: 33678312 DOI: 10.1016/j.semnephrol.2020.12.004] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Kidney disease, especially when it is associated with a reduction in estimated glomerular filtration rate, can be associated with an increase in serum urate (uric acid), suggesting that hyperuricemia in subjects with kidney disease may be a strictly secondary phenomenon. Mendelian randomization studies that evaluate genetic scores regulating serum urate also generally have not found evidence that serum urate is a causal risk factor in chronic kidney disease. Nevertheless, this is countered by a large number of epidemiologic, experimental, and clinical studies that have suggested a potentially important role for uric acid in kidney disease and cardiovascular disease. Here, we review the topic in detail. Overall, the studies strongly suggest that hyperuricemia does have an important pathogenic role that likely is driven by intracellular urate levels. An exception may be the role of extracellular uric acid in atherosclerosis and vascular calcification. One of the more striking findings on reviewing the literature is that the primary benefit of lowering serum urate in subjects with CKD is not by slowing the progression of renal disease, but rather by reducing the incidence of cardiovascular events and mortality. We recommend large-scale clinical trials to determine if there is a benefit in lowering serum urate in hyperuricemic subjects in acute and chronic kidney disease and in the reduction of cardiovascular morbidity and mortality in subjects with end-stage chronic kidney disease.
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5
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Pan J, Shi M, Ma L, Fu P. Mechanistic Insights of Soluble Uric Acid-related Kidney Disease. Curr Med Chem 2020; 27:5056-5066. [PMID: 30526453 DOI: 10.2174/0929867326666181211094421] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 11/21/2018] [Accepted: 12/03/2018] [Indexed: 02/07/2023]
Abstract
Hyperuricemia, defined as the presence of elevated serum uric acid (sUA), could lead to urate deposit in joints, tendons, kidney and other tissues. Hyperuricemia as an independent risk factor was common in patients during the causation and progression of kidney disease. Uric acid is a soluble final product of endogenous and dietary purine metabolism, which is freely filtered in kidney glomeruli where approximately 90% of filtered uric acid is reabsorbed. Considerable studies have demonstrated that soluble uric acid was involved in the pathophysiology of renal arteriolopathy, tubule injury, tubulointerstitial fibrosis, as well as glomerular hypertrophy and glomerulosclerosis. In the review, we summarized the mechanistic insights of soluble uric acid related renal diseases.
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Affiliation(s)
- Jing Pan
- Kidney Research Laboratory, Division of Nephrology, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Min Shi
- Kidney Research Laboratory, Division of Nephrology, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Liang Ma
- Kidney Research Laboratory, Division of Nephrology, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, China
| | - Ping Fu
- Kidney Research Laboratory, Division of Nephrology, National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu 610041, China
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Sellmayr M, Hernandez Petzsche MR, Ma Q, Krüger N, Liapis H, Brink A, Lenz B, Angelotti ML, Gnemmi V, Kuppe C, Kim H, Bindels EMJ, Tajti F, Saez-Rodriguez J, Lech M, Kramann R, Romagnani P, Anders HJ, Steiger S. Only Hyperuricemia with Crystalluria, but not Asymptomatic Hyperuricemia, Drives Progression of Chronic Kidney Disease. J Am Soc Nephrol 2020; 31:2773-2792. [PMID: 32938648 DOI: 10.1681/asn.2020040523] [Citation(s) in RCA: 88] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Accepted: 07/24/2020] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND The roles of asymptomatic hyperuricemia or uric acid (UA) crystals in CKD progression are unknown. Hypotheses to explain links between UA deposition and progression of CKD include that (1) asymptomatic hyperuricemia does not promote CKD progression unless UA crystallizes in the kidney; (2) UA crystal granulomas may form due to pre-existing CKD; and (3) proinflammatory granuloma-related M1-like macrophages may drive UA crystal-induced CKD progression. METHODS MALDI-FTICR mass spectrometry, immunohistochemistry, 3D confocal microscopy, and flow cytometry were used to characterize a novel mouse model of hyperuricemia and chronic UA crystal nephropathy with granulomatous nephritis. Interventional studies probed the role of crystal-induced inflammation and macrophages in the pathology of progressive CKD. RESULTS Asymptomatic hyperuricemia alone did not cause CKD or drive the progression of aristolochic acid I-induced CKD. Only hyperuricemia with UA crystalluria due to urinary acidification caused tubular obstruction, inflammation, and interstitial fibrosis. UA crystal granulomas surrounded by proinflammatory M1-like macrophages developed late in this process of chronic UA crystal nephropathy and contributed to the progression of pre-existing CKD. Suppressing M1-like macrophages with adenosine attenuated granulomatous nephritis and the progressive decline in GFR. In contrast, inhibiting the JAK/STAT inflammatory pathway with tofacitinib was not renoprotective. CONCLUSIONS Asymptomatic hyperuricemia does not affect CKD progression unless UA crystallizes in the kidney. UA crystal granulomas develop late in chronic UA crystal nephropathy and contribute to CKD progression because UA crystals trigger M1-like macrophage-related interstitial inflammation and fibrosis. Targeting proinflammatory macrophages, but not JAK/STAT signaling, can attenuate granulomatous interstitial nephritis.
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Affiliation(s)
- Markus Sellmayr
- Division of Nephrology, Department of Medicine IV, Ludwig-Maximilian's-University Hospital, Munich, Germany
| | | | - Qiuyue Ma
- Division of Nephrology, Department of Medicine IV, Ludwig-Maximilian's-University Hospital, Munich, Germany
| | - Nils Krüger
- Division of Nephrology, Department of Medicine IV, Ludwig-Maximilian's-University Hospital, Munich, Germany
| | - Helen Liapis
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri (retired) and Arkana Laboratories, Little Rock, Arkansas
| | - Andreas Brink
- Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland
| | - Barbara Lenz
- Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Basel, Switzerland
| | - Maria Lucia Angelotti
- Excellence Centre for Research, Transfer and High Education for the Development of DE NOVO Therapies (DENOTHE), University of Florence, Florence, Italy
| | - Viviane Gnemmi
- Department of Pathology, University Hospital, Centre Hospitalier Régional Universitaire, Lille, France
| | - Christoph Kuppe
- Division of Nephrology and Clinical Immunology, Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany
| | - Hyojin Kim
- Faculty of Medicine, Rheinisch-Westfälische Technische Hochschule, Aachen University, Joint Research Centre for Computational Biomedicine (JRC-COMBINE), Aachen, Germany
| | | | - Ferenc Tajti
- Division of Nephrology and Clinical Immunology, Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany.,Faculty of Medicine, Rheinisch-Westfälische Technische Hochschule, Aachen University, Joint Research Centre for Computational Biomedicine (JRC-COMBINE), Aachen, Germany
| | - Julio Saez-Rodriguez
- Faculty of Medicine, Rheinisch-Westfälische Technische Hochschule, Aachen University, Joint Research Centre for Computational Biomedicine (JRC-COMBINE), Aachen, Germany.,Faculty of Medicine, Institute for Computational Biomedicine, Heidelberg University, and Heidelberg University Hospital, Heidelberg, Germany
| | - Maciej Lech
- Division of Nephrology, Department of Medicine IV, Ludwig-Maximilian's-University Hospital, Munich, Germany
| | - Rafael Kramann
- Division of Nephrology and Clinical Immunology, Rheinisch-Westfälische Technische Hochschule Aachen University, Aachen, Germany.,Department of Internal Medicine, Nephrology and Transplantation, Erasmus Medical Center, Rotterdam, The Netherlands
| | - Paola Romagnani
- Excellence Centre for Research, Transfer and High Education for the Development of DE NOVO Therapies (DENOTHE), University of Florence, Florence, Italy.,Nephrology and Dialysis Unit, Meyer Children's University Hospital, Florence, Italy
| | - Hans-Joachim Anders
- Division of Nephrology, Department of Medicine IV, Ludwig-Maximilian's-University Hospital, Munich, Germany
| | - Stefanie Steiger
- Division of Nephrology, Department of Medicine IV, Ludwig-Maximilian's-University Hospital, Munich, Germany
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Bardin T, Nguyen QD, Tran KM, Le NH, Do MD, Richette P, Letavernier E, Correas JM, Resche-Rigon M. A cross-sectional study of 502 patients found a diffuse hyperechoic kidney medulla pattern in patients with severe gout. Kidney Int 2020; 99:218-226. [PMID: 32898570 DOI: 10.1016/j.kint.2020.08.024] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 08/18/2020] [Accepted: 08/27/2020] [Indexed: 12/27/2022]
Abstract
We have previously shown that ultrasonography can detect hyperechogenic crystal deposits in the kidney medulla of patients with gout. In this cross-sectional study we investigated the frequency and clinical correlates of hyperechogenic kidney medulla in 502 consecutive primary consultants for gout (ACR/EULAR criteria) at the Vien Gut medical center in Ho Chi Minh City, Vietnam. None of these patients received urate-lowering drugs. Kidney medulla echogenicity on B-mode ultrasonography was compared to that of the kidney cortex. Overall, 36% patients showed a hyperechoic pattern of Malpighi pyramids. On univariate analysis, the pattern was significantly associated with age, estimated gout duration, steroid-dependency, clinical tophi, urate arthropathy, double contour thickness at the scanned joints, coronary heart disease, arterial hypertension, hyperuricemia, proteinuria, leukocyturia, and decreased estimated glomerular filtration rate. On multivariable analysis, the hyperechoic pattern was associated with estimated disease duration, clinical tophi, urate arthropathy, double contour thickness and decreased estimated glomerular filtration rate. No hyperechoic pattern was observed in 515 consecutive consultants without gout. Thus, hyperechoic kidney medulla was frequently demonstrated in Vietnamese patients with tophaceous gout and associated with features of tubulointerstitial nephritis. This finding revives the hypothesis of microcrystalline nephropathy of gout, predominantly seen in untreated gouty patients, which could be an important target for urate-lowering therapy.
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Affiliation(s)
- Thomas Bardin
- French-Vietnamese Research Center on Gout and Chronic Diseases, Vien Gut Medical Center, Ho Chi Minh City, Vietnam; Department of Rheumatology, Hôpital Lariboisière APHP, Paris, France; Université de Paris, INSERM U1132, Paris, France.
| | - Quang D Nguyen
- French-Vietnamese Research Center on Gout and Chronic Diseases, Vien Gut Medical Center, Ho Chi Minh City, Vietnam
| | - Khoy M Tran
- French-Vietnamese Research Center on Gout and Chronic Diseases, Vien Gut Medical Center, Ho Chi Minh City, Vietnam
| | - Nghia H Le
- French-Vietnamese Research Center on Gout and Chronic Diseases, Vien Gut Medical Center, Ho Chi Minh City, Vietnam
| | - Minh D Do
- Center for Molecular Biomedicine, University of Medicine and Pharmacy at Ho Chi Min City, Vietnam
| | - Pascal Richette
- Department of Rheumatology, Hôpital Lariboisière APHP, Paris, France; Université de Paris, INSERM U1132, Paris, France
| | - Emmanuel Letavernier
- Department of Physiology, Hôpital Tenon, APHP, Paris, France; Sorbonne Université and INSERM, UMR S 1155, Hôpital Tenon, Paris, France
| | - Jean-Michel Correas
- Department of Radiology, Hôpital Necker, APHP, Paris, France; Université de Paris, Paris, France
| | - Mathieu Resche-Rigon
- French-Vietnamese Research Center on Gout and Chronic Diseases, Vien Gut Medical Center, Ho Chi Minh City, Vietnam; Department of Biostatistics, Hôpital Saint Louis, APHP, Paris, France; Université de Paris, UMR U1153 ECSTRA team INERM, Paris, France
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8
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Kaewput W, Thongprayoon C, Rangsin R, Ruangkanchanasetr P, Bathini T, Mao MA, Cheungpasitporn W. Association between serum uric acid and chronic kidney disease in patients with hypertension: A multicenter nationwide cross-sectional study. J Evid Based Med 2019; 12:235-242. [PMID: 31482688 DOI: 10.1111/jebm.12364] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2019] [Revised: 07/04/2019] [Accepted: 08/04/2019] [Indexed: 12/01/2022]
Abstract
INTRODUCTION Current data on the role of hyperuricemia as a risk factor for renal progression in patients with hypertension is inconclusive. This study aimed to assess the association of uric acid and chronic kidney disease (CKD) in hypertensive patients using a nationwide patient sample. METHODS We conducted a nationwide cross-sectional study based on the DM/HT study of the Medical Research Network of the Consortium of Thai Medical Schools. This study evaluated adult patients with hypertension from 831 Thailand public hospitals in the year 2014. Serum uric acid (SUA) was categorized into quintiles (≤4.5, 4.6 to 5.4, 5.5 to 6.2, 6.3 to 7.4, ≥7.5 mg/dL). CKD was defined as estimated glomerular filtration rate of ≤ 60 mL/min/1.73 m2 . Multivariate logistic regression was performed to assess the association between SUA and CKD using uric acid of ≤4.5 mg/dL as the reference group. RESULTS A total of 9776 hypertensive patients with available SUA were included in the analysis. The mean SUA was 6.1±1.8 mg/dL. The prevalence of CKD in hypertensive patients was 31.8%. SUA of 4.6 to 5.4, 5.5 to 6.2, 6.3 to 7.4, and ≥7.5 mg/dL were associated with an increased CKD with ORs of 1.57 (95% CI 1.28 to 1.92), 2.15 (95% CI 1.74 to 2.66), 3.31 (95% CI 2.72 to 4.04), and 7.11 (95% CI 5.76 to 8.78), respectively. The restricted cubic spline showed significant increased CKD prevalence when uric acid ≥4.6 mg/dL. CONCLUSION Higher SUA was associated with increased CKD prevalence in patients with hypertension. SUA should be monitored in hypertensive patients for CKD prevention.
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Affiliation(s)
- Wisit Kaewput
- Department of Military and Community Medicine, Phramongkutklao College of Medicine, Bangkok, Thailand
| | - Charat Thongprayoon
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota
| | - Ram Rangsin
- Department of Military and Community Medicine, Phramongkutklao College of Medicine, Bangkok, Thailand
| | - Prajej Ruangkanchanasetr
- Division of Nephrology, Department of Medicine, Phramongkutklao Hospital and College of Medicine, Bangkok, Thailand
| | - Tarun Bathini
- Department of Internal Medicine, University of Arizona, Tucson, Arizona
| | - Michael A Mao
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Jacksonville, Florida
| | - Wisit Cheungpasitporn
- Division of Nephrology, Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi
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9
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Sato Y, Feig DI, Stack AG, Kang DH, Lanaspa MA, Ejaz AA, Sánchez-Lozada LG, Kuwabara M, Borghi C, Johnson RJ. The case for uric acid-lowering treatment in patients with hyperuricaemia and CKD. Nat Rev Nephrol 2019; 15:767-775. [PMID: 31296965 DOI: 10.1038/s41581-019-0174-z] [Citation(s) in RCA: 122] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/12/2019] [Indexed: 02/07/2023]
Abstract
Hyperuricaemia is common among patients with chronic kidney disease (CKD), and increases in severity with the deterioration of kidney function. Although existing guidelines for CKD management do not recommend testing for or treatment of hyperuricaemia in the absence of a diagnosis of gout or urate nephrolithiasis, an emerging body of evidence supports a direct causal relationship between serum urate levels and the development of CKD. Here, we review randomized clinical trials that have evaluated the effect of urate-lowering therapy (ULT) on the rate of CKD progression. Among trials in which individuals in the control arm experienced progressive deterioration of kidney function (which we define as ≥4 ml/min/1.73 m² over the course of the study - typically 6 months to 2 years), treatment with ULT conferred consistent clinical benefits. In contrast, among trials where clinical progression was not observed in the control arm, treatment with ULT was ineffective, but this finding should not be used as an argument against the use of uric acid-lowering therapy. Although additional studies are needed to identify threshold values of serum urate for treatment initiation and to confirm optimal target levels, we believe that sufficient evidence exists to recommend routine measurement of serum urate levels in patients with CKD and consider initiation of ULT among those who are hyperuricaemic with evidence of deteriorating renal function, unless specific contraindications exist.
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Affiliation(s)
- Yuka Sato
- Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Daniel I Feig
- Division of Pediatric Nephrology, University of Alabama, Birmingham, AL, USA
| | - Austin G Stack
- Division of Nephrology, Department of Medicine, University Hospital Limerick, Limerick, Ireland.,Graduate Entry Medical School, University of Limerick, Limerick, Ireland
| | - Duk-Hee Kang
- Division of Nephrology, Department of Internal Medicine, Ewha Womans University College of Medicine Ewha Medical Research Center, Seoul, South Korea
| | - Miguel A Lanaspa
- Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - A Ahsan Ejaz
- Division of Nephrology, Hypertension and Renal Transplantation, University of Florida, Gainesville, FL, USA
| | - L Gabriela Sánchez-Lozada
- Laboratory of Renal Physiopathology, Department of Nephrology, INC Ignacio Chavez, Mexico City, Mexico
| | - Masanari Kuwabara
- Department of Cardiology and Intensive Care Unit, Toranomon Hospital, Tokyo, Japan
| | - Claudio Borghi
- Department of Medicine, University of Bologna, Bologna, Italy
| | - Richard J Johnson
- Division of Renal Diseases and Hypertension, University of Colorado Anschutz Medical Campus, Aurora, CO, USA. .,Rocky Mountain Regional VA Medical Center, Aurora, CO, USA.
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10
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Towiwat P, Chhana A, Dalbeth N. The anatomical pathology of gout: a systematic literature review. BMC Musculoskelet Disord 2019; 20:140. [PMID: 30935368 PMCID: PMC6444644 DOI: 10.1186/s12891-019-2519-y] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Accepted: 03/20/2019] [Indexed: 02/14/2023] Open
Abstract
Background The aim of this systematic literature review was to comprehensively describe the anatomical pathology of tissues affected by gout. Methods We searched PubMed, The Cochrane Library, Excerpta Medica Database (EMBASE), and Web of Science Core Collection for all English language articles published before March 2018. Articles were included if they described the microscopic or macroscopic appearances of gout in human tissue. Results Four hundred and seventeen articles met inclusion criteria and were included in the review. Articles describing the anatomical pathology of gout in musculoskeletal structures, including bone, tendon and ligaments, synovium and cartilage, were most common. Articles describing skin and kidney pathology in gout were also common, with pathology in other sites such as visceral organs less common. At all sites, monosodium urate crystal deposition was reported, and the tophus was also described within many different tissues. During a gout flare, diffuse acute neutrophilic synovial inflammation was evident. The tophus was described as an organised chronic giant cell granulomatous structure consisting of monosodium urate crystals, innate and adaptive immune cells, and fibrovascular tissue. Conclusions Consistent with the clinical presentation of gout, most studies describing the anatomical pathology of gout report involvement of musculoskeletal structures, with monosodium urate crystal deposition and tophus the most common lesions described. This review details the anatomical pathology features of gout at affected sites. Electronic supplementary material The online version of this article (10.1186/s12891-019-2519-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Patapong Towiwat
- Department of Medicine, University of Auckland, Auckland, New Zealand. .,Department of Medicine, Naresuan University, Phitsanulok, 65000, Thailand.
| | - Ashika Chhana
- Department of Medicine, University of Auckland, Auckland, New Zealand
| | - Nicola Dalbeth
- Department of Medicine, University of Auckland, Auckland, New Zealand
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11
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Bardin T, Tran KM, Nguyen QD, Sarfati M, Richette P, Vo NT, Bousson V, Correas JM. Renal medulla in severe gout: typical findings on ultrasonography and dual-energy CT study in two patients. Ann Rheum Dis 2019; 78:433-434. [PMID: 30269050 DOI: 10.1136/annrheumdis-2018-214174] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Revised: 09/05/2018] [Accepted: 09/07/2018] [Indexed: 11/03/2022]
Affiliation(s)
- Thomas Bardin
- French-Vietnamese Research Center on Gout and Chronic diseases, Vien Gut Medical Clinic, Ho Chi Minh City, Vietnam
- Rheumatology Department, Hôpital Lariboisière APHP, Paris, France
- Université Paris Diderot, INSERM U1132, Paris, France
| | - Khoi Minh Tran
- French-Vietnamese Research Center on Gout and Chronic diseases, Vien Gut Medical Clinic, Ho Chi Minh City, Vietnam
| | - Quang Dinh Nguyen
- French-Vietnamese Research Center on Gout and Chronic diseases, Vien Gut Medical Clinic, Ho Chi Minh City, Vietnam
| | - Marine Sarfati
- Rheumatology Department, Hôpital Lariboisière APHP, Paris, France
| | - Pascal Richette
- Rheumatology Department, Hôpital Lariboisière APHP, Paris, France
- Université Paris Diderot, INSERM U1132, Paris, France
| | | | - Valérie Bousson
- Université Paris Diderot, CNRS UMR 7052, Paris, France
- Radiology Department, Hôpital Lariboisière APHP, Paris, France
| | - Jean-Michel Correas
- Radiology Department, Hôpital Necker APHP, Paris, France
- Paris Descartes University, Paris, France
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Viggiano D, Gigliotti G, Vallone G, Giammarino A, Nigro M, Capasso G. Urate-Lowering Agents in Asymptomatic Hyperuricemia: Role of Urine Sediment Analysis and Musculoskeletal Ultrasound. Kidney Blood Press Res 2018; 43:606-615. [DOI: 10.1159/000489145] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2017] [Accepted: 04/12/2018] [Indexed: 11/19/2022] Open
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Eleftheriadis T, Golphinopoulos S, Pissas G, Stefanidis I. Asymptomatic hyperuricemia and chronic kidney disease: Narrative review of a treatment controversial. J Adv Res 2017; 8:555-560. [PMID: 28748122 PMCID: PMC5512148 DOI: 10.1016/j.jare.2017.05.001] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2017] [Revised: 04/23/2017] [Accepted: 05/01/2017] [Indexed: 02/07/2023] Open
Abstract
Today there is plausible evidence both on experimental and epidemiological basis, that hyperuricemia represents a risk factor for the development and progression of chronic kidney disease (CKD). Nevertheless, the role of serum uric acid lowering treatment in CKD is still a matter of serious controversy. Review of randomised controlled trials, suggests that there may be an improvement of renal function with allopurinol treatment in CKD stage 3-5. However, these studies have included a relatively limited number of participants and provide insufficient information on adverse events and on the incidence of the end stage renal disease. Therefore, before adequately powered randomised, placebo-controlled trials are completed we cannot recommend treating asymptomatic hyperuricemia in patients with CKD.
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Affiliation(s)
| | | | | | - Ioannis Stefanidis
- Department of Nephrology, University of Thessaly, School of Medicine, Mezourlo Hill, 41110 Larissa, Greece
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Sharaf El Din UA, Salem MM, Abdulazim DO. Uric acid in the pathogenesis of metabolic, renal, and cardiovascular diseases: A review. J Adv Res 2017; 8:537-548. [PMID: 28748119 PMCID: PMC5512153 DOI: 10.1016/j.jare.2016.11.004] [Citation(s) in RCA: 242] [Impact Index Per Article: 30.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2016] [Revised: 11/26/2016] [Accepted: 11/27/2016] [Indexed: 02/07/2023] Open
Abstract
The association between uric acid (UA) on one side and systemic hypertension (Htn), dyslipidemia, glucose intolerance, overweight, fatty liver, renal disease and cardiovascular disease (CVD) on the other side is well recognized. However, the causal relationship between UA and these different clinical problems is still debatable. The recent years have witnessed hundreds of experimental and clinical trials that favored the opinion that UA is a probable player in the pathogenesis of these disease entities. These studies disclosed the strong association between hyperuricemia and metabolic syndrome (MS), obesity, Htn, type 2 diabetes mellitus (DM), non-alcoholic fatty liver disease, hypertriglyceridemia, acute kidney injury, chronic kidney disease (CKD), coronary heart disease (CHD), heart failure and increased mortality among cardiac and CKD patients. The association between UA and nephrolithiasis or preeclampsia is a non-debatable association. Recent experimental trials have disclosed different changes in enzyme activities induced by UA. Nitric oxide (NO) synthase, adenosine monophosphate kinase (AMPK), adenosine monophosphate dehydrogenase (AMPD), and nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase are affected by UA. These changes in enzymatic activities can lead to the observed biochemical and pathological changes associated with UA. The recent experimental, clinical, interventional, and epidemiologic trials favor the concept of a causative role of UA in the pathogenesis of MS, renal, and CVDs.
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Affiliation(s)
- Usama A.A. Sharaf El Din
- Nephrology Unit, Internal Medicine Department, School of Medicine, Cairo University, Egypt
- Corresponding author. Fax: +20 222753890.
| | - Mona M. Salem
- Endocrinology Unit, Internal Medicine Department, School of Medicine, Cairo University, Egypt
| | - Dina O. Abdulazim
- Rheumatology and Rehabilitation Department, School of Medicine, Cairo University, Egypt
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Perreault S, Nuevo J, Baumgartner S, Morlock R. Any link of gout disease control among hypertensive patients and onset of end-stage renal disease? Results from a population-based study. World J Nephrol 2017; 6:132-142. [PMID: 28540203 PMCID: PMC5424435 DOI: 10.5527/wjn.v6.i3.132] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Revised: 08/02/2016] [Accepted: 10/27/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To determine the impact of allopurinol non-adherence as a proxy for uncontrolled disease on primary prevention of end-stage renal disease (ESRD).
METHODS A cohort of 2752 patients with gout diagnosis was reconstructed using the Québec Régie de l’assurance maladie du Québec and MedEcho administrative databases. Eligible patients were new users of allopurinol, aged 45-85, with a diagnosis of hypertension, and treated with an antihypertensive drug between 1997 and 2007.
RESULTS Major risk factor for ESRD onset was chronic kidney disease at stages 1 to 3 [rate ratio (RR) = 8.00; 95% confidence interval (CI): 3.16-22.3 and the severity of hypertension (≥ 3 vs < 3 antihypertensives)] was a trending risk factor as a crude estimate (RR = 1.94; 95%CI: 0.68-5.51). Of 341 patients, cases (n = 22) and controls (n = 319), high adherence level (≥ 80%) to allopurinol therapy, compared with lower adherence level (< 80%), was associated with a lower rate of ESRD onset (RR = 0.35; 95%CI: 0.13-0.91).
CONCLUSION Gout control seem to be associated with a significant decreased risk of ESRD onset in hypertensive populations, further research should be conducted confirming this potential associated risk.
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Moudi E, Hosseini SR, Bijani A. Nephrolithiasis in elderly population; effect of demographic characteristics. J Nephropathol 2016; 6:63-68. [PMID: 28491855 PMCID: PMC5418072 DOI: 10.15171/jnp.2017.11] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Accepted: 12/03/2016] [Indexed: 12/22/2022] Open
Abstract
Background Kidney stone (nephrolithiasis) is one of the most common diseases. During the past several decades, its prevalence and incidence have increased markedly in elderly population. Objectives This study was conducted to evaluate the risk factors for nephrolithiasis in elderly population. Patients and Methods This study was based on the Amirkola Health and Ageing Project (AHAP). Elderly people with kidney stones in every size, type and number were considered to be the case group and other subjects without a history of kidney stones served as control group. Demographic and anthropometric data, smoking, diabetes and metabolic syndrome (MetS), calcium (Ca), vitamin D, parathyroid hormone (PTH), uric acid and urine pH were compared in both groups. Results
In this study, 1390 elderly people with the mean age of 69.37 ± 7.42 years were evaluated which 202 (14.53%) cases had renal stones. The patients with nephrolithiasis were younger (P = 0.010) and had higher uric acid and body mass index (BMI) levels (P = 0.041 and P = 0.006, respectively). Age <75 years, male gender and BMI ≥30 kg/m2 had a significant association with stone formation. The prevalence of diabetes, MetS and smoking in the patients with nephrolithiasis was lower than the subjects without it.
Conclusions This study suggests that male gender, obesity and age <75 years might be independent risk factors for the development of nephrolithiasis. Hence, low animal protein intake and weight reduction should be included as part of the counseling of senior stone-formers.
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Affiliation(s)
- Emadoddin Moudi
- Department of Urology, Shahid Beheshti Hospital, Babol University of Medical Sciences, Babol, Iran
| | - Seyed Reza Hosseini
- Social Determinants of Health Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Ali Bijani
- General physician, Social Determinants of Health Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
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Abstract
Hyperuricemia (elevated serum uric acid) is prevalent, and an important mediator of gout, an increasingly common condition. In addition, hyperuricemia is associated with metabolic syndrome, diabetes, hypertension, and kidney and cardiovascular diseases. Although it remains controversial whether hyperuricemia is a causal factor for kidney disease, the kidneys play a major role in the regulation of serum uric acid levels. Approximately two-thirds of the uric acid produced in humans is excreted by the kidneys. The handling of urate in the renal proximal tubule is extensive, as uric acid undergoes filtration, reabsorption, and secretion. Variations in renal urate handling have been shown to influence the risk of gout. In observational studies, hyperuricemia has been shown to predict kidney disease onset and progression, with a variety of mechanisms implicated. Because of this close association between hyperuricemia and kidney disease, and due to limited studies on the topic, it is important to conduct future studies on the treatment of hyperuricemia to slow kidney disease progression and improve cardiovascular survival in patients with chronic kidney disease. Furthermore, it is important to monitor for gout in patients with kidney disease and to follow the guidelines for treatment of hyperuricemia in this group of patients. This narrative review provides an in-depth discussion of the link between serum uric acid levels, renal handling of uric acid, and diseases associated with dysfunction in uric acid homeostasis.
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Yan D, Tu Y, Jiang F, Wang J, Zhang R, Sun X, Wang T, Wang S, Bao Y, Hu C, Jia W. Uric Acid is independently associated with diabetic kidney disease: a cross-sectional study in a Chinese population. PLoS One 2015; 10:e0129797. [PMID: 26029914 PMCID: PMC4451151 DOI: 10.1371/journal.pone.0129797] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2015] [Accepted: 05/13/2015] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Association between hyperuricaemia and chronic kidney disease has been studied widely, but the influence of uric acid on the kidneys remains controversial. We aimed to summarize the association between uric acid and diabetic kidney disease (DKD), and to evaluate the role of uric acid in DKD. METHODS We enrolled 3,212 type 2 diabetic patients in a cross-sectional study. The patients' basic characteristics (sex, age, BMI, duration of disease, and blood pressure) and chemical parameters (triglycerides, total cholesterol, low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), microalbuminuria, creatinine, and uric acid) were recorded, and the association between uric acid and DKD was evaluated. RESULTS In the 3,212 diabetic patients, the prevalence of diabetic kidney disease was higher in hyperuricaemic patients than in patients with normouricaemia (68.3% vs 41.5%). The prevalence of DKD increased with increasing uric acid (p < 0.0001). Logistic analysis identified uric acid as an independent predictor of DKD (p < 0.0001; adjusted OR (95%CI) = 1.005 (1.004-1.007), p < 0.0001). Uric acid was positively correlated with albuminuria and creatinine levels (p < 0.0001) but negatively correlated with eGFR (p < 0.0001) after adjusting for confounding factors. CONCLUSIONS Hyperuricaemia is a risk factor for DKD. Serum uric acid levels within the high-normal range are independently associated with DKD.
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Affiliation(s)
- Dandan Yan
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
| | - Yinfang Tu
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
| | - Feng Jiang
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
| | - Jie Wang
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
| | - Rong Zhang
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
| | - Xue Sun
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
| | - Tao Wang
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
| | - Shiyun Wang
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
| | - Yuqian Bao
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
| | - Cheng Hu
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
- Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, South Branch, Shanghai, China
- * E-mail: (CH); (WJ)
| | - Weiping Jia
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Center for Diabetes, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China
- * E-mail: (CH); (WJ)
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Abstract
In gouty patients, urate lowering therapies (ULTs) are recommended to bring serum uric acid (SUA) levels below 6.0 mg/dL, with the aim of dissolving urate depositions, thereby reducing disease impact. However, patients with hyperuricemia often present with other conditions associated with cardiovascular (CV) risk, such as high blood pressure, obesity, insulin resistance, fatty liver, and chronic kidney disease. In the last decade, several well grounded pieces of evidence showed that the elevation of uric acid often occurs prior to the development of hypertension or metabolic syndrome, thus suggesting a direct association between elevated SUA and these conditions. This paper will discuss available evidence supporting the key role of serum uric acid in the development of CV and renal disease, with a focus on the molecular mechanisms underlying this causative association. This review is based on a PubMed/Embase database search for articles on hyperuricemia and its impact on cardiovascular and renal function.
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Su J, Wei Y, Liu M, Liu T, Li J, Ji Y, Liang J. Anti-hyperuricemic and nephroprotective effects of Rhizoma Dioscoreae septemlobae extracts and its main component dioscin via regulation of mOAT1, mURAT1 and mOCT2 in hypertensive mice. Arch Pharm Res 2014; 37:1336-44. [DOI: 10.1007/s12272-014-0413-6] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2014] [Accepted: 05/13/2014] [Indexed: 12/01/2022]
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The role of uric acid in kidney fibrosis: experimental evidences for the causal relationship. BIOMED RESEARCH INTERNATIONAL 2014; 2014:638732. [PMID: 24877124 PMCID: PMC4026934 DOI: 10.1155/2014/638732] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/27/2014] [Revised: 04/05/2014] [Accepted: 04/21/2014] [Indexed: 02/07/2023]
Abstract
Hyperuricemia is a common finding in chronic kidney disease due to decreased uric acid clearance. The role of uric acid as a risk factor for chronic kidney disease has been largely debated, and recent studies suggested a role of uric acid in the causation and progression of kidney fibrosis, a final common pathway in chronic kidney disease. Uric acid and xanthine oxidase may contribute to kidney fibrosis mainly by inducing inflammation, endothelial dysfunction, oxidative stress, and activation of the renin-angiotensin system. Besides, hyperuricemia induces alterations in renal hemodynamics via afferent arteriolopathy and contributes to the onset and progression of kidney fibrosis. Xanthine oxidase inhibitors may prevent kidney damage via lowering uric acid and/or inhibiting xanthine oxidase. However, there is still no sufficient evidence from interventional clinical researches supporting the causal relationship between uric acid and kidney fibrosis. The effect and role of xanthine oxidase inhibitors in preventing kidney fibrosis and chronic kidney disease progression must be further explored by performing future large scale clinical trials.
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Miyaoka T, Mochizuki T, Takei T, Tsuchiya K, Nitta K. Serum uric acid levels and long-term outcomes in chronic kidney disease. Heart Vessels 2013; 29:504-12. [PMID: 23929090 DOI: 10.1007/s00380-013-0396-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2013] [Accepted: 07/25/2013] [Indexed: 12/20/2022]
Abstract
Hyperuricemia is common in chronic kidney disease (CKD), but data regarding the relationship between serum uric acid levels and the long-term outcomes of CKD patients have been limited. The present study evaluated the associations between baseline serum uric acid levels with mortality and end-stage renal disease (ESRD). The subjects of this study were 551 stage 2-4 CKD patients. Cox proportional hazards models were used to evaluate the relationship between serum uric acid tertiles and all-cause mortality, cardiovascular disease (CVD) mortality, 50 % reduction in estimated glomerular filtration rate (eGFR), and development of ESRD, initially without adjustment, and then after adjusting for several groups of covariates. The mean age of the study subjects was 58.5 years, 59.3 % were men, and 10.0 % had diabetes. The mean eGFR was 42.02 ± 18.52 ml/min/1.73 m(2). In all subjects, the mean serum uric acid level was 6.57 ± 1.35 mg/dl, and 52.2 % of study subjects were on hypouricemic therapy (allopurinol; 48.3 %) at baseline. Thirty-one patients (6.1 %) died during a follow-up period of approximately 6 years. There was no significant association between serum uric acid level and all-cause mortality, CVD mortality, development of ESRD and 50 % reduction in eGFR in the unadjusted Cox models. In the adjusted models, hyperuricemia was found to be associated with all-cause mortality and CVD mortality after adjustment with CVD risk factors, kidney disease factors, and allopurinol, but not associated with development of ESRD and 50 % reduction in eGFR. The results of this study showed that hyperuricemia but not serum uric acid levels were associated with all-cause mortality, CVD mortality after adjustments with CVD risk factors, kidney disease factors, and allopurinol in stage 2-4 CKD patients.
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Affiliation(s)
- Tokiko Miyaoka
- Department of Medicine, Kidney Center, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo, 162-8666, Japan
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Johnson RJ, Nakagawa T, Jalal D, Sánchez-Lozada LG, Kang DH, Ritz E. Uric acid and chronic kidney disease: which is chasing which? Nephrol Dial Transplant 2013; 28:2221-8. [PMID: 23543594 DOI: 10.1093/ndt/gft029] [Citation(s) in RCA: 419] [Impact Index Per Article: 34.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Serum uric acid is commonly elevated in subjects with chronic kidney disease (CKD), but was historically viewed as an issue of limited interest. Recently, uric acid has been resurrected as a potential contributory risk factor in the development and progression of CKD. Most studies documented that an elevated serum uric acid level independently predicts the development of CKD. Raising the uric acid level in rats can induce glomerular hypertension and renal disease as noted by the development of arteriolosclerosis, glomerular injury and tubulointerstitial fibrosis. Pilot studies suggest that lowering plasma uric acid concentrations may slow the progression of renal disease in subjects with CKD. While further clinical trials are necessary, uric acid is emerging as a potentially modifiable risk factor for CKD. Gout was considered a cause of CKD in the mid-nineteenth century, and, prior to the availability of therapies to lower the uric acid level, the development of end-stage renal disease was common in gouty patients. In their large series of gouty subjects Talbott and Terplan found that nearly 100% had variable degrees of CKD at autopsy (arteriolosclerosis, glomerulosclerosis and interstitial fibrosis). Additional studies showed that during life impaired renal function occurred in half of these subjects. As many of these subjects had urate crystals in their tubules and interstitium, especially in the outer renal medulla, the disease became known as gouty nephropathy. The identity of this condition fell in question as the presence of these crystals may occur in subjects without renal disease; furthermore, the focal location of the crystals could not explain the diffuse renal scarring present. In addition, many subjects with gout also had coexistent conditions such as hypertension and vascular disease, leading some experts to suggest that the renal injury in gout was secondary to these latter conditions rather than to uric acid per se. Indeed, gout was removed from the textbooks as a cause of CKD, and the common association of hyperuricemia with CKD was solely attributed to the retention of serum uric acid that is known to occur as the glomerular filtration rate falls. Renewed interest in uric acid as a cause of CKD occurred when it was realized that invalid assumptions had been made in the arguments to dismiss uric acid as a risk factor for CKD. The greatest assumption was that the mechanism by which uric acid would cause kidney disease would be via the precipitation as crystals in the kidney, similar to the way it causes gout. However, when laboratory animals with CKD were made hyperuricemic, the renal disease progressed rapidly despite an absence of crystals in the kidney. Since this seminal study, there has been a renewed interest in the potential role uric acid may have in both acute and CKD. We briefly review some of the major advances that have occurred in this field in the last 15 years.
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Affiliation(s)
- Richard J Johnson
- Division of Kidney Diseases and Hypertension, University of Colorado Denver, Aurora, CO, USA
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Bleyer AJ, Kmoch S. Gout: a step forward. Adv Chronic Kidney Dis 2012; 19:356-7. [PMID: 23089269 DOI: 10.1053/j.ackd.2012.07.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2012] [Accepted: 07/24/2012] [Indexed: 11/11/2022]
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Shi YW, Wang CP, Wang X, Zhang YL, Liu L, Wang RW, Ye JF, Hu LS, Kong LD. Uricosuric and nephroprotective properties of Ramulus Mori ethanol extract in hyperuricemic mice. JOURNAL OF ETHNOPHARMACOLOGY 2012; 143:896-904. [PMID: 22967667 DOI: 10.1016/j.jep.2012.08.023] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/25/2011] [Revised: 07/09/2012] [Accepted: 08/16/2012] [Indexed: 06/01/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Ramulus Mori, the branch of Morus alba, is widely used in traditional Chinese medicine prescriptions to treat gout and hyperuricemia. AIM OF THIS STUDY To evaluate the uricosuric and nephroprotective effects of ethanol extract of Ramulus Mori (ERM) and explore its possible mechanisms in hyperuricemic mice. MATERIALS AND METHODS HPLC analysis was employed to determine the main constituents. Hyperuricemia was induced by potassium oxonate (250 mg/kg) in male mice. ERM (10, 20 and 40 mg/kg) was orally administered to hyperuricemic and normal mice for 7 days. Serum and urine levels of uric acid, creatinine and blood urea nitrogen (BUN) were measured. Simultaneously, renal mRNA and protein levels of mouse urate transporter 1 (mURAT1), glucose transporter 9 (mGLUT9), organic anion transporter 1 (mOAT1) and organic cation/carnitine transporters (mOCT1/2, mOCTN1/2) were analyzed by RT-PCR and Western blotting methods. RESULTS ERM mainly contained mulberroside A, oxyresveratrol, 4-hydroxycinnamic acid, resveratrol, 7-hydroxycumarin and morin. ERM significantly reduced serum urate levels and increased 24h-urine urate excretion and fractional excretion of uric acid in hyperuricemic mice. It effectively restored oxonate-induced expression alteration of renal mURAT1, mGLUT9 and mOAT1, resulting in urate excretion enhancement. Moreover, ERM decreased serum creatinine and BUN levels and increased creatinine clearance, and up-regulated expression of mOCT1/2 and mOCTN1/2, contributing to kidney function improvement in this model. CONCLUSION These results suggest that ERM exerts the uricosuric and nephroprotective actions by the regulation of these renal organic ion transporters in hyperuricemic mice, and provide scientific support for the empirical use of Ramulus Mori.
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Affiliation(s)
- Yun-Wei Shi
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, PR China
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Abstract
Although an elevation of serum uric acid level is often associated with chronic kidney disease (CKD), it remains controversial whether hyperuricemia per se is a true risk factor for the development or aggravation of CKD. Recent epidemiologic studies in healthy populations or in subjects with established kidney disease have reported the independent role of uric acid in lowering glomerular filtration rate and increasing the risk for new-onset kidney disease. Furthermore, lowering uric acid in patients with established renal disease has been reported to stabilize renal function independent of other confounders, suggesting a causative role of elevated uric acid in progression of CKD, rather than as an incidental finding related to CKD severity. In this manuscript we will discuss the potential role of uric acid in the development and aggravation of CKD based on epidemiologic, clinical and experimental studies. Given the worldwide epidemic of CKD, the importance of identifying modifiable risk factors of CKD, and the clinical implication of hyperuricemia in CKD, we propose large randomized clinical trials to investigate whether uric acid-lowering therapy can slow the progression of CKD.
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Affiliation(s)
- Duk-Hee Kang
- Division of Nephrology, Department of Internal Medicine, Ewha Womans University School of Medicine, Ewha Medical Research Center, Seoul, Korea.
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Filiopoulos V, Hadjiyannakos D, Vlassopoulos D. New insights into uric acid effects on the progression and prognosis of chronic kidney disease. Ren Fail 2012; 34:510-20. [PMID: 22260409 DOI: 10.3109/0886022x.2011.653753] [Citation(s) in RCA: 86] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Hyperuricemia is particularly common in patients with arterial hypertension, metabolic syndrome, or kidney disease. Its role, however, as a risk factor for both renal and cardiovascular outcomes and in the context of the well-established interrelationship between cardiovascular disease and chronic kidney disease (CKD) is debated. For decades high serum uric acid levels were mainly considered the result of renal dysfunction and not a true mediator of renal disease development and progression. However, recent epidemiological studies suggest an independent association between asymptomatic hyperuricemia and increased risk of arterial hypertension, CKD, cardiovascular events, and mortality. Furthermore, data from experimental models of hyperuricemia have provided robust evidence in this direction. Hyperuricemia causes increased arterial pressure, proteinuria, renal dysfunction, and progressive renal and vascular disease in rats. The main pathophysiological mechanisms of these deleterious effects caused by uric acid are endothelial dysfunction, activation of local renin-angiotensin system, increased oxidative stress, and proinflammatory and proliferative actions. A small number of short-term, single-center clinical studies support the beneficial influence of pharmaceutical reduction of serum uric acid on total cardiovascular risk, as well as on renal disease development and progression. Hyperuricemia is probably related to the incidence of primary hypertension in children and adolescents, as serum uric acid lowering by allopurinol has an antihypertensive action in this group of patients. Finally, it is clear that adequately powered randomized controlled trials are urgently required to elucidate the role of uric acid in cardiovascular events and outcomes, as well as in the development and progression of CKD.
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Johnson RJ, Kanbay M, Sánchez-Lozada LG. The Rediscovery of Uric Acid in Cardiorenal Disease: Introduction. Semin Nephrol 2011; 31:391-3. [DOI: 10.1016/j.semnephrol.2011.08.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Bellomo G, Venanzi S, Verdura C, Saronio P, Esposito A, Timio M. Association of uric acid with change in kidney function in healthy normotensive individuals. Am J Kidney Dis 2010; 56:264-72. [PMID: 20385436 DOI: 10.1053/j.ajkd.2010.01.019] [Citation(s) in RCA: 181] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2009] [Accepted: 01/21/2010] [Indexed: 02/08/2023]
Abstract
BACKGROUND Despite recent evidence, the role of uric acid as a causal factor in the pathogenesis and progression of kidney disease remains controversial, partly because of the inclusion in epidemiologic studies of patients with hypertension, diabetes, and/or proteinuria. STUDY DESIGN Prospective observational cohort. SETTING & PARTICIPANTS 900 healthy normotensive adult blood donors (153 women, 747 men) evaluated at baseline and after 5 years. PREDICTOR Serum uric acid level. OUTCOMES Decrease in estimated glomerular filtration rate (eGFR) >10 mL/min/1.73 m(2), computed using the Modification of Diet in Renal Disease (MDRD) Study equation, with secondary analyses examining similar decreases using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and Cockcroft-Gault equations. RESULTS During a median follow-up of 59 months, eGFR decreased from 97 +/- 16 to 88 +/- 14 mL/min/1.73 m(2). Higher serum uric acid levels were associated with a greater likelihood of eGFR decrease in both women and men (HR, 1.13 [95% CI, 1.04-1.39] per each 1-mg/dL increase in uric acid level); in multivariable analyses adjusting for age, sex, body mass index, blood glucose level, total cholesterol level, mean blood pressure, urine albumin-creatinine ratio, and serum triglyceride level, the association remained highly significant (HR, 1.28 [95% CI, 1.12-1.48]). Results were similar using different estimating equations and when the association was examined in sex-specific subgroups. LIMITATIONS Analyses were based on a single baseline uric acid measurement. Women are underrepresented. CONCLUSIONS In healthy normotensive individuals, serum uric acid level is an independent risk factor for decreased kidney function.
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Affiliation(s)
- Gianni Bellomo
- Department of Nephrology, San Giovanni Battista Hospital, Foligno, Pg, Italy.
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Abstract
The question of whether hyperuricemia can induce chronic direct renal injury has been argued for many decades. Despite continued efforts and strong motivations to seek an answer, the current evidence still cannot definitively prove or refute the hypothesis. Recent data in rodents do favor causality between hyperuricemia and renal disease. Human epidemiologic data are quite varied, but positive studies do exist. Pathophysiologic models of biology for this entity are sparse in animals and nonexistent in humans.
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Affiliation(s)
- Orson W Moe
- Department of Internal Medicine, Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, Dallas, TX 75390-8855, USA.
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Abstract
In humans, uric acid is the main urinary metabolite of purines. Serum levels are higher compared with other mammalians. Uric acid is an antioxidant and perhaps helps to control blood pressure during a low Na+ diet through stimulation of the renin-angiotensin system. Serum uric acid is also considered a marker of tubular reabsorption and 'effective' circulating blood volume. Moreover, hyperuricemia seems to be a cofactor in Na+ -sensitive hypertension, a marker and possibly itself responsible for microvascular damage through stimulation of the renin-angiotensin system, inhibition of endothelial nitric oxide, and proliferative effects on vascular smooth muscle. As fructose-rich diets increase uric acid levels, hyperuricemia may also play a role in the metabolic syndrome, triggering insulin resistance and hypertension.A number of studies on rats rendered hyperuricemic by administration of uricase inhibitors have recently confirmed induction of arterial hypertension and microvascular injury, particularly in the remnant kidney or in cyclosporine-induced renal fibrosis.
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Gaffo AL, Saag KG. Management of hyperuricemia and gout in CKD. Am J Kidney Dis 2008; 52:994-1009. [PMID: 18971014 DOI: 10.1053/j.ajkd.2008.07.035] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2008] [Accepted: 07/21/2008] [Indexed: 02/07/2023]
Affiliation(s)
- Angelo L Gaffo
- Birmingham VA Medical Center, University of Alabama at Birmingham, AL, USA
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Mohandas R, Johnson RJ. Uric acid levels increase risk for new-onset kidney disease. J Am Soc Nephrol 2008; 19:2251-3. [PMID: 18971373 DOI: 10.1681/asn.2008091012] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
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Abstract
Rheumatologists care for patients with gouty arthritis, a condition caused by chronic and uncontrolled hyperuricaemia. Hyperuricaemia, gout and renal dysfunction are often bedfellows, raising the possibility of the former causing the latter. We sought the answer to the question 'Among patients with normal measures of glomerular filtration, does hyperuricaemia predict future renal disease'? We identified prospective cohort studies evaluating the relationship between serum uric acid and chronic kidney function from the past 20 yrs, through MEDLINE, Cochrane Library and EMBASE searches and bibliography cross-referencing. Nine cohort studies that met the selection criteria were found. Because of the extreme heterogeneity, a statistical meta-analysis was not performed. Most (eight out of nine) studies found an independent risk factor for deterioration of kidney function. Nearly all published prospective studies support the role of hyperuricaemia as an independent risk factor for renal dysfunction. In the absence of large randomized controlled trials of uric acid reduction, it remains uncertain if this relation is causal or merely an epiphenomenon. Regardless, our review suggests that hyperuricaemia is a useful, inexpensively measured, widely available and useful early marker for chronic kidney disease.
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Affiliation(s)
- Z Avram
- Division of Rheumatology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
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Su BYJ, Lai HM, Chen CJ, Chen YC, Chiu CK, Lin KM, Yu SF, Cheng TT. Ischemia heart disease and greater waist circumference are risk factors of renal function deterioration in male gout patients. Clin Rheumatol 2007; 27:581-6. [DOI: 10.1007/s10067-007-0750-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2007] [Revised: 09/12/2007] [Accepted: 09/13/2007] [Indexed: 10/22/2022]
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Abstract
The interrelationship between uric acid and renal disease is reviewed in a historical context. Four phases can be distinguished--the descriptions of uric acid stones and gravel in the eighteenth century, of chronically scarred kidneys containing urate crystals in the nineteenth, the appearance of the syndrome of acute urate nephropathy following tumour lysis in the mid twentieth century, and finally the realization that soluble urate affects both systemic and glomerular blood vessels, and may play a role in both hypertension and chronic renal damage.
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Affiliation(s)
- J Stewart Cameron
- Renal Unit, Guy's Hospital, Guy's King's and St Thomas' Medical School, King's College, London, UK.
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Tsouli SG, Liberopoulos EN, Mikhailidis DP, Athyros VG, Elisaf MS. Elevated serum uric acid levels in metabolic syndrome: an active component or an innocent bystander? Metabolism 2006; 55:1293-301. [PMID: 16979398 DOI: 10.1016/j.metabol.2006.05.013] [Citation(s) in RCA: 186] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2005] [Accepted: 05/04/2006] [Indexed: 12/13/2022]
Abstract
Elevated serum uric acid (SUA) levels are commonly seen in patients with the metabolic syndrome (MetS). Several mechanisms, both direct and indirect, connect the increased SUA levels with the established diagnostic criteria of MetS. It is possible that the increased cardiovascular disease risk associated with the MetS is partially attributed to elevated circulating SUA concentration. Several drugs used in the treatment of MetS may alter SUA levels. Thus, lifestyle measures together with the judicious selection of drugs for the treatment of hypertension, dyslipidemia, and insulin resistance associated with MetS may result in a reduction of SUA levels and possibly cardiovascular disease risk. This review summarizes the pathophysiologic association between SUA and MetS and focuses on the prevention of hyperuricemia and its cardiovascular consequences.
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Affiliation(s)
- Sofia G Tsouli
- Department of Internal Medicine, School of Medicine, University of Ioannina, 45110 Ioannina, Greece
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Nakagawa T, Kang DH, Feig D, Sanchez-Lozada LG, Srinivas TR, Sautin Y, Ejaz AA, Segal M, Johnson RJ. Unearthing uric acid: An ancient factor with recently found significance in renal and cardiovascular disease. Kidney Int 2006; 69:1722-5. [PMID: 16598194 DOI: 10.1038/sj.ki.5000391] [Citation(s) in RCA: 123] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Uric acid is strongly associated with cardiovascular and renal disease, but is usually not considered to have a causal role. However, recent experimental, epidemiological, and clinical studies provocatively suggest that uric acid may contribute to the development of hypertension, metabolic syndrome, and kidney disease in some patients. Clinical studies are urgently needed to examine this important possibility.
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Affiliation(s)
- T Nakagawa
- Division of Nephrology, Hypertension, and Renal Transplantation, University of Florida, Gainesville, 32610, USA.
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Siu YP, Leung KT, Tong MKH, Kwan TH. Use of allopurinol in slowing the progression of renal disease through its ability to lower serum uric acid level. Am J Kidney Dis 2006; 47:51-9. [PMID: 16377385 DOI: 10.1053/j.ajkd.2005.10.006] [Citation(s) in RCA: 578] [Impact Index Per Article: 30.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2005] [Accepted: 10/03/2005] [Indexed: 02/07/2023]
Abstract
BACKGROUND Hyperuricemia is associated strongly with the development of hypertension, renal disease, and progression. Allopurinol decreases serum uric acid levels by inhibiting the enzyme xanthine oxidase. We hypothesized that administrating allopurinol to decrease serum uric acid levels to the normal range in hyperuricemic patients with chronic kidney disease may be of benefit in decreasing blood pressure and slowing the rate of renal disease progression in these patients. METHODS We conducted a prospective, randomized, controlled trial of 54 hyperuricemic patients with chronic kidney disease. Patients were randomly assigned to treatment with allopurinol, 100 to 300 mg/d, or to continue the usual therapy for 12 months. Clinical, hematologic, and biochemical parameters were measured at baseline and 3, 6, and 12 months of treatment. We define our study end points as: (1) stable kidney function with less than 40% increase in serum creatinine level, (2) impaired renal function with creatinine level increase greater than 40% of baseline value, (3) initiation of dialysis therapy, and (4) death. RESULTS One patient in the treatment group dropped out because of skin allergy to allopurinol. Serum uric acid levels were significantly decreased in subjects treated with allopurinol, from 9.75 +/- 1.18 mg/dL (0.58 +/- 0.07 mmol/L) to 5.88 +/- 1.01 mg/dL (0.35 +/- 0.06 mmol/L; P < 0.001). There were no significant differences in systolic or diastolic blood pressure at the end of the study comparing the 2 groups. There was a trend toward a lower serum creatinine level in the treatment group compared with controls after 12 months of therapy, although it did not reach statistical significance (P = 0.08). Overall, 4 of 25 patients (16%) in the allopurinol group reached the combined end points of significant deterioration in renal function and dialysis dependence compared with 12 of 26 patients (46.1%) in the control group (P = 0.015). CONCLUSION Allopurinol therapy significantly decreases serum uric acid levels in hyperuricemic patients with mild to moderate chronic kidney disease. Its use is safe and helps preserve kidney function during 12 months of therapy compared with controls. Results of this study need to be confirmed with an additional prospective trial involving a larger cohort of patients to determine the long-term efficacy of allopurinol therapy and in specific chronic kidney disease subpopulations.
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Affiliation(s)
- Yui-Pong Siu
- Division of Nephrology, Department of Medicine, Tuen Mun Hospital, Hong Kong, China
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42
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Kang DH, Han L, Ouyang X, Kahn AM, Kanellis J, Li P, Feng L, Nakagawa T, Watanabe S, Hosoyamada M, Endou H, Lipkowitz M, Abramson R, Mu W, Johnson RJ. Uric acid causes vascular smooth muscle cell proliferation by entering cells via a functional urate transporter. Am J Nephrol 2005; 25:425-33. [PMID: 16113518 DOI: 10.1159/000087713] [Citation(s) in RCA: 169] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2005] [Accepted: 07/05/2005] [Indexed: 11/19/2022]
Abstract
BACKGROUND Soluble uric acid stimulates vascular smooth muscle cell (VSMC) proliferation by activating mitogen-activated protein kinases, and stimulating COX-2 and PDGF synthesis. The mechanism by which uric acid enters the VSMC is not known. We hypothesized that uric acid enters via transporters similar to that observed in the kidney. METHODS We studied the uptake of uric acid into rat VSMC under polarized and depolarized conditions and in the presence of organic anion transport (OAT) inhibitors (probenecid and benzbromarone) or p-aminohippurate (PAH). We also examined the ability of probenecid to inhibit uric acid-induced VSMC proliferation and monocyte chemoattractant protein-1 (MCP-1) synthesis. RESULTS (14)C-Urate uptake was shown in VSMC and was enhanced under depolarized conditions. (14)C-Uric acid uptake was inhibited by probenecid and benzbromarone, as well as by unlabelled urate and PAH. Probenecid blocked VSMC proliferation and MCP-1 expression in response to uric acid. VSMC did not express rOAT1-3, rOAT-5 or URAT-1 mRNA by PCR, but did express the voltage-sensitive transporter (UAT) by both PCR and RNase protection assay. CONCLUSIONS Urate enters VSMC by both voltage-sensitive and OAT pathways, and the uptake, cell proliferation and MCP-1 expression can be blocked by OAT inhibitors. The specific transporter(s) responsible for the urate uptake remains to be determined.
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Affiliation(s)
- Duk-Hee Kang
- Division of Nephrology, Ewha Women's University College of Medicine, Seoul, Korea
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Johnson RJ, Segal MS, Srinivas T, Ejaz A, Mu W, Roncal C, Sánchez-Lozada LG, Gersch M, Rodriguez-Iturbe B, Kang DH, Acosta JH. Essential hypertension, progressive renal disease, and uric acid: a pathogenetic link? J Am Soc Nephrol 2005; 16:1909-19. [PMID: 15843466 DOI: 10.1681/asn.2005010063] [Citation(s) in RCA: 205] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Hypertension and hypertension-associated ESRD are epidemic in society. The mechanisms responsible for renal progression in mild to moderate hypertension and those groups most at risk need to be identified. Historic, epidemiologic, clinical, and experimental studies on the pathogenesis of hypertension and hypertension-associated renal disease are reviewed and an overview/hypothesis for the mechanisms involved in renal progression is presented. There is increasing evidence that hypertension may exist in one of two forms/stages. The first stage, most commonly observed in early or borderline hypertension, is characterized by salt-resistance, normal or only slightly decreased GFR, relatively normal or mild renal arteriolosclerosis, and normal renal autoregulation. This group is at minimal risk for renal progression. The second stage, characterized by salt-sensitivity, renal arteriolar disease, and blunted renal autoregulation, defines a group at highest risk for the development of microalbuminuria, albuminuria, and progressive renal disease. This second stage is more likely to be observed in blacks, in subjects with gout or hyperuricemia, with low level lead intoxication, or with severe obesity/metabolic syndrome. The two major mechanistic pathways for causing impaired autoregulation at mild to moderate elevations in BP appear to be hyperuricemia and/or low nephron number. Understanding the pathogenetic pathways mediating renal progression in hypertensive subjects should help identify those subjects at highest risk and may provide insights into new therapeutic maneuvers to slow or prevent progression.
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Affiliation(s)
- Richard J Johnson
- University of Florida, Division of Nephrology, Hypertension, and Transplantation, 1600 SW Archer Road, Gainesville, FL 32610, USA.
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Kang DH, Nakagawa T. Uric acid and chronic renal disease: Possible implication of hyperuricemia on progression of renal disease. Semin Nephrol 2005; 25:43-9. [PMID: 15660334 DOI: 10.1016/j.semnephrol.2004.10.001] [Citation(s) in RCA: 106] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Although hyperuricemia has long been associated with renal disease, uric acid has not been considered as a true mediator of progression of renal disease. The observation that hyperuricemia commonly is associated with other risk factors of cardiovascular and renal disease, especially hypertension, has made it difficult to dissect the effect of uric acid itself. However, recent epidemiologic evidence suggests a significant and independent association between the level of serum uric acid and renal disease progression with beneficial effect of decreasing uric acid levels. Furthermore, our experimental data using hyperuricemic animals and cultured cells have provided robust evidence regarding the role of uric acid on progression of renal disease. Hyperuricemia increased systemic blood pressure, proteinuria, renal dysfunction, vascular disease, and progressive renal scarring in rats. Recent data also suggest hyperuricemia may be one of the key and previously unknown mechanisms for the activation of the renin-angiotensin and cyclooxygenase-2 (COX-2) systems in progressive renal disease. Although we must be cautious in the interpretation of animal models to human disease, these studies provide a mechanism to explain epidemiologic data that show uric acid is an independent risk factor for renal progression. Although there is no concrete evidence yet that uric acid bears a causal or reversible relationship to progressive renal disease in humans, it is time to reevaluate the implication of hyperuricemia as an important player for progression of renal disease and to try to find safe and reasonable therapeutic modalities in individual patients based on their clinical data, medication history, and the presence of cardiovascular complications.
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Affiliation(s)
- Duk-Hee Kang
- Division of Nephrology, Ewha Women's University College of Medicine, Seoul 110-126, Korea.
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45
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Vázquez-Mellado J, Alvarez Hernández E, Burgos-Vargas R. Primary prevention in rheumatology: the importance of hyperuricemia. Best Pract Res Clin Rheumatol 2004; 18:111-24. [PMID: 15121034 DOI: 10.1016/j.berh.2004.01.001] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hyperuricemia (HU) is present in 5-30% of the general population, although the prevalence is higher among some ethnic groups and seems to be increasing worldwide. Classically, chronic HU has been considered a risk factor for gout or lithiasis and is associated with alcoholism, obesity, hypertension, dyslipidemia, hyperglycemia/diabetes mellitus, renal failure and intake of certain drugs. HU is also associated with cardiovascular diseases such as hypertension, vascular disease, pre-eclampsia, pulmonary arterial hypertension, stroke, heart failure, ischemic heart disease and also metabolic syndrome, renal disease and increased mortality. It is uncertain if these associations are dependent or not, especially cardiovascular and renal diseases. Patients with chronic HU and also those with gout require both medical investigation for associated diseases or drugs as well as nutritional counseling and life-style changes. HU should alert physicians to possible complications.
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Affiliation(s)
- Janitzia Vázquez-Mellado
- Rheumatology Service, Hospital General de México, Faculty of Medicine, Universidad Nacional Autónoma de México, Dr. Balmis 148, Col. Doctores, 06726 México City, Mexico.
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46
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Abstract
A substantial body of epidemiological and experimental evidence suggests that serum uric acid is an important, independent risk factor for cardiovascular and renal disease especially in patients with hypertension, heart failure, or diabetes. Elevated serum uric acid is highly predictive of mortality in patients with heart failure or coronary artery disease and of cardiovascular events in patients with diabetes. Further, patients with hypertension and hyperuricemia have a 3- to 5-fold increased risk of experiencing coronary artery disease or cerebrovascular disease compared with patients with normal uric acid levels. Although the mechanisms by which uric acid may play a pathogenetic role in cardiovascular disease is unclear, hyperuricemia is associated with deleterious effects on endothelial dysfunction, oxidative metabolism, platelet adhesiveness, hemorheology, and aggregation. Xanthine oxidase inhibitors (e.g., allopurinol) or a variety of uricosuric agents (e.g., probenecid, sulfinpyrazone, benzbromarone, and benziodarone) can lower elevated uric acid levels but it is unknown whether these agents reversibly impact cardiovascular outcomes. However, the findings of the recent LIFE study in patients with hypertension and left ventricular hypertrophy suggest the possibility that a treatment-induced decrease in serum uric acid may indeed attenuate cardiovascular risk. LIFE showed that approximately 29% (14% to 107%, p = 0.004) of the treatment benefit of a losartan-based versus atenolol-based therapy on the primary composite endpoint (death, myocardial infarction, or stroke) may be ascribed to differences in achieved serum uric acid levels. Overall, serum uric acid may be a powerful tool to help stratify risk for cardiovascular disease. At the very least, it should be carefully considered when evaluating overall cardiovascular risk.
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Affiliation(s)
- Michael Alderman
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461-1602, USA.
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Chang SJ, Chen CJ, Hung HP, Ou TT, Ko YC. Community-based study in Taiwan aborigines concerning renal dysfunction in gout patients. Scand J Rheumatol 2004; 33:233-8. [PMID: 15370718 DOI: 10.1080/03009740310004919] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
OBJECTIVE To reveal the factors associated with renal dysfunction among gout patients in Taiwan aborigines. METHODS Social demographic data, alcohol consumption data, anthropometric measurements, blood samples, and 24-h urine samples were collected from 128 aboriginals (101 men, 27 women) suffering from gout. RESULTS The men displayed higher mean creatinine clearance (Ccr) values than women. Twenty-two post-menopausal women had significantly lower Ccr values compared to the five pre-menopausal women [probability (p)<0.001]. The males displayed higher 24-h urinary creatinine value than females (8.60+/-5.39 versus 5.58+/-2.14 mmol/L; p<0.05), and showed a significantly higher positive relationship between 24-h urinary creatinine and uric acid excretion [correlation coefficient (r)=0.7304; p<0.001], whereas the females did not (r=0.1144; p=0.5691). Overall, those who were older members of the Tsou tribe, or had excreted less uric acid from urine in 24 h tended to suffer renal dysfunction. CONCLUSIONS Gout patients displayed diversity in renal function. An exogenous source of creatinine in men was more likely than in women.
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Affiliation(s)
- S J Chang
- Department of Public Health, School of Medicine, Kaohsiung Medical University, Taiwan
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Johnson RJ, Kang DH, Feig D, Kivlighn S, Kanellis J, Watanabe S, Tuttle KR, Rodriguez-Iturbe B, Herrera-Acosta J, Mazzali M. Is there a pathogenetic role for uric acid in hypertension and cardiovascular and renal disease? Hypertension 2003; 41:1183-90. [PMID: 12707287 DOI: 10.1161/01.hyp.0000069700.62727.c5] [Citation(s) in RCA: 909] [Impact Index Per Article: 41.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Hyperuricemia is associated with hypertension, vascular disease, renal disease, and cardiovascular events. In this report, we review the epidemiologic evidence and potential mechanisms for this association. We also summarize experimental studies that demonstrate that uric acid is not inert but may have both beneficial functions (acting as an antioxidant) as well as detrimental actions (to stimulate vascular smooth muscle cell proliferation and induce endothelial dysfunction). A recently developed experimental model of mild hyperuricemia also provides the first provocative evidence that uric acid may have a pathogenic role in the development of hypertension, vascular disease, and renal disease. Thus, it is time to reevaluate the role of uric acid as a risk factor for cardiovascular disease and hypertension and to design human studies to address this controversy.
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Affiliation(s)
- Richard J Johnson
- Division of Nephrology, Baylor College of Medicine, SM-1273, 6550 Fannin St, Houston, Tex 77030, USA.
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Sánchez-Lozada LG, Tapia E, Avila-Casado C, Soto V, Franco M, Santamaría J, Nakagawa T, Rodríguez-Iturbe B, Johnson RJ, Herrera-Acosta J. Mild hyperuricemia induces glomerular hypertension in normal rats. Am J Physiol Renal Physiol 2002; 283:F1105-10. [PMID: 12372787 DOI: 10.1152/ajprenal.00170.2002] [Citation(s) in RCA: 210] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Mildly hyperuricemic rats develop renin-dependent hypertension and interstitial renal disease. Hyperuricemia might also induce changes in glomerular hemodynamics. Micropuncture experiments under deep anesthesia were performed in Sprague-Dawley rats fed a low-salt diet (LS group), fed a low-salt diet and treated with oxonic acid (OA/LS group), and fed a low-salt diet and treated with oxonic acid + allopurinol (OA/LS/AP group) for 5 wk. The OA/LS group developed hyperuricemia and hypertension compared with the LS group: 3.1 +/- 0.2 vs. 1.1 +/- 0.2 mg/dl (P < 0.01) and 143 +/- 4 vs. 126 +/- 2 mmHg (P < 0.01). Hyperuricemic rats developed increased glomerular capillary pressure compared with the LS rats: 56.7 +/- 1.2 vs. 51.9 +/- 1.4 mmHg (P < 0.05). Pre- and postglomerular resistances were not increased. Histology showed afferent arteriolar thickening with increased alpha-smooth muscle actin staining of the media. Allopurinol prevented hyperuricemia (1.14 +/- 0.2 mg/dl), systemic (121.8 +/- 2.8 mmHg) and glomerular hypertension (50.1 +/- 0.8 mmHg), and arteriolopathy in oxonic acid-treated rats. Linear regression analysis showed that glomerular capillary pressure and arteriolar thickening correlated positively with serum uric acid and systolic blood pressure. Glomerular hypertension may be partially mediated by an abnormal vascular response to systemic hypertension due to arteriolopathy of the afferent arteriole.
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Affiliation(s)
- Laura G Sánchez-Lozada
- Department of Nephrology, Instituto Nacional de Cardiologia I Chavez, 14080 Mexico City, Mexico.
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Abstract
Increased serum urate concentration is commonly seen in clinical practice. It does not represent a specific disease, nor is it an indication for therapy. Hyperuricemia can be the consequence of increased uric acid production and/or decreased renal capacity to excrete uric acid. In essential hypertension, it has been described in up to one third of patients and is directly related to an increase in renal vascular resistance and inversely correlated with renal plasma flow. In other words, abnormal renal hemodynamics, commonly seen in the initial stages of the disease, account for the increased serum urate concentration. This can be maintained if a decrease in glomerular filtration rate takes place. The increase in uric acid has been shown to be a potent predictor of the development of cardiovascular events and death. In addition, uric acid, particularly when elevated, could represent an independent risk factor. On the other hand, an altered renal function predicts in an independent manner a higher cardiovascular risk. For this reason, the predictive capacity of uric acid could be partly dependent on the fact that hyperuricemia runs in parallel with a deranged renal function.
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Affiliation(s)
- L M Ruilope
- Unidad de Hipertensión, Hospital 12 de Octubre, 28041, Madrid, Spain.
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